Cited by 790Inflammasome and immune disordersImmune Response and InflammationAutoimmune and Inflammatory Disorders Research

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The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response

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Baroja-Mazo, Alberto, Martín-Sánchez, Fatima, Gomez, Ana I, Martínez, Carlos M, Amores-Iniesta, Joaquín, Compan, Vincent, Barberà-Cremades, Maria, Yagüe, Jordi, Ruiz-Ortiz, Estibaliz, Antón, Jordi, Buján, Segundo, Couillin, Isabelle, Brough, David, Arostegui, Juan I, Pelegrín, Pablo·2014·Nature Immunology

DOI 10.1038/ni.2919

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Abstract

Assembly of the NLRP3 inflammasome activates caspase-1 and mediates the processing and release of the leaderless cytokine IL-1β and thereby serves a central role in the inflammatory response and in diverse human diseases. Here we found that upon activation of caspase-1, oligomeric NLRP3 inflammasome particles were released from macrophages. Recombinant oligomeric protein particles composed of the adaptor ASC or the p.D303N mutant form of NLRP3 associated with cryopyrin-associated periodic syndromes (CAPS) stimulated further activation of caspase-1 extracellularly, as well as intracellularly after phagocytosis by surrounding macrophages. We found oligomeric ASC particles in the serum of patients with active CAPS but not in that of patients with other inherited autoinflammatory diseases. Our findings support a model whereby the NLRP3 inflammasome, acting as an extracellular oligomeric complex, amplifies the inflammatory response.

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Additional file 4 of Spatiotemporal evolution of pyroptosis and canonical inflammasome pathway in hSOD1G93A ALS mouse model
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Additional file 6 of Spatiotemporal evolution of pyroptosis and canonical inflammasome pathway in hSOD1G93A ALS mouse model
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Additional file 5 of Spatiotemporal evolution of pyroptosis and canonical inflammasome pathway in hSOD1G93A ALS mouse model
Zhang, H., Li, H., Huang, B., Wang, S., Gao, Y., Meng, F., Chen, Y., Zhou, F., Guan, Y., & Wang, X. (2022) · Figshare · doi:10.6084/m9.figshare.20462427
Additional file 2 of Microglial PGC-1α protects against ischemic brain injury by suppressing neuroinflammation
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Additional file 5 of Evolutionary analyses of the gasdermin family suggest conserved roles in infection response despite loss of pore-forming functionality
Angosto-Bazarra, D., Alarcón‐Vila, C., Hurtado‐Navarro, L., Baños, M. C., Rivers‐Auty, J., & Pelegrı́n, P. (2022) · Figshare · doi:10.6084/m9.figshare.18070873
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Additional file 1 of Microglial PGC-1α protects against ischemic brain injury by suppressing neuroinflammation
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Additional file 3 of Spatiotemporal evolution of pyroptosis and canonical inflammasome pathway in hSOD1G93A ALS mouse model
Zhang, H., Li, H., Huang, B., Wang, S., Gao, Y., Meng, F., Chen, Y., Zhou, F., Guan, Y., & Wang, X. (2022) · Figshare · doi:10.6084/m9.figshare.20462421
Additional file 2 of IC100: a novel anti-ASC monoclonal antibody improves functional outcomes in an animal model of multiple sclerosis
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Additional file 2 of Directly targeting ASC by lonidamine alleviates inflammasome-driven diseases
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Additional file 1 of Evolutionary analyses of the gasdermin family suggest conserved roles in infection response despite loss of pore-forming functionality
Angosto-Bazarra, D., Alarcón‐Vila, C., Hurtado‐Navarro, L., Baños, M. C., Rivers‐Auty, J., & Pelegrı́n, P. (2022) · Figshare · doi:10.6084/m9.figshare.18070858
Additional file 7 of Spatiotemporal evolution of pyroptosis and canonical inflammasome pathway in hSOD1G93A ALS mouse model
Zhang, H., Li, H., Huang, B., Wang, S., Gao, Y., Meng, F., Chen, Y., Zhou, F., Guan, Y., & Wang, X. (2022) · Figshare · doi:10.6084/m9.figshare.20462433
Additional file 8 of Evolutionary analyses of the gasdermin family suggest conserved roles in infection response despite loss of pore-forming functionality
Angosto-Bazarra, D., Alarcón‐Vila, C., Hurtado‐Navarro, L., Baños, M. C., Rivers‐Auty, J., & Pelegrı́n, P. (2022) · Figshare · doi:10.6084/m9.figshare.18070882
Additional file 2 of Spatiotemporal evolution of pyroptosis and canonical inflammasome pathway in hSOD1G93A ALS mouse model
Zhang, H., Li, H., Huang, B., Wang, S., Gao, Y., Meng, F., Chen, Y., Zhou, F., Guan, Y., & Wang, X. (2022) · Figshare · doi:10.6084/m9.figshare.20462418
Additional file 1 of Directly targeting ASC by lonidamine alleviates inflammasome-driven diseases
Chen, C., Zhou, Y., Ning, X., Li, S., Xue, D., Wei, C., Zhu, Z., Sheng, L., Lu, B., Li, Y., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26557928
Additional file 1 of ASC specks exacerbate α‑synuclein pathology via amplifying NLRP3 inflammasome activities
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Additional file 1 of Spatiotemporal evolution of pyroptosis and canonical inflammasome pathway in hSOD1G93A ALS mouse model
Zhang, H., Li, H., Huang, B., Wang, S., Gao, Y., Meng, F., Chen, Y., Zhou, F., Guan, Y., & Wang, X. (2022) · Figshare · doi:10.6084/m9.figshare.20462415
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“Similarly, ASC and mutant NLRP3 particles have been shown by others to retain pro-inflammatory activity after being released from pyroptotic macrophages [23].”
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Mašalaitė, K., Norkienė, M., Žvirblienė, A., & Lučiūnaitė, A. (2026) · European Journal of Immunology · doi:10.1002/eji.70199
“NLRP3 inflammasome consists of three major components—the NLRP3 receptor, apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC), and autoproteolytically activating caspase-1 [ 4 ].”
Targeting the NLRP3 inflammasome with antibody-based therapeutics for chronic neurodegenerative diseases
Sandhu, J. K., Tanha, J., & Arbabi‐Ghahroudi, M. (2026) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2026.2671675 · Cited by 1
“NLRP3 signaling is further amplified by extracellular ASC specks, released from activated microglia [27,28].”
CMPK2 promotes M1 macrophage polarization in sepsis-induced acute lung injury via NLRP3/NF-κB signalling
Li, C., Ding, P., Zheng, Z., Wei, H., Yang, Y., Chen, D., Li, Y., & Yang, R. (2026) · International Immunopharmacology · doi:10.1016/j.intimp.2026.116906
Therapeutic Silencing of Tmprss6 Reduces Iron‐Induced Inflammation and Prolongs Survival in MDS Mice
Vilcassim, S., Pholngam, N., Thubthed, R., Nualkaew, T., Svasti, S., Chaichompoo, P., Kysenius, K., Crouch, P. J., Dames, S., Eisermann, M., et al. (2026) · American Journal of Hematology · doi:10.1002/ajh.70391
“Moreover, the extracellular release of ASC specks from pyroptotic cells can further propagate inflammation, underscoring the broad impact of inflammasome activation on disease progression [16, 17].”
Efficacy of hyaluronic acid and butyroyl glutathione in the management of glaucoma-related ocular surface disease: a prospective, interventional, double-blind, cross-over post market study
Afflitto, G. G., Fanelli, M., Petrone, V., Chirico, R., Ceccarelli, F., Martucci, A., Minutolo, A., Aiello, F., Garaci, E., Matteucci, C., et al. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1780815
The Dual Role of Exosomes in Gout: From Inflammatory Amplifiers to Therapeutic Regulators
Gao, X., Zhang, J., Kong, X., Xue, Y., & Fan, W. (2026) · Inflammation · doi:10.1007/s10753-026-02551-1 · Cited by 1
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Bhuyan, F., Bradfield, C. J., Roy, A., de Jesus, A. A., Rahman, M. A., Schwarz, B. H., Gasilina, A., Rastegar, A. T., Gaurav, S., Friend, C., et al. (2026) · medRxiv · doi:10.64898/2026.08.04.26358821
Prospects for treatment of cerebral ischemic stroke with Hydroxysafflower Yellow A
Chen, B., Zhang, Y., Zhai, C., Ma, C., & Song, L. (2026) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2026.109103
The inflammasome adaptor protein ASC present differential intracellular and extracellular functions to trigger immunometabolic dysregulation and dysbiosis during obesity
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Serum NLRP3 levels are associated with postoperative delirium of elderly patients with lung cancer: an observational analytical study
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Authors: Baroja-Mazo, A., Martín-Sánchez, F., Gomez, A. I., Martínez, C. M., Amores-Iniesta, J., Compan, V., Barberà-Cremades, M., Yagüe, J., Ruiz-Ortiz, E., Antón, J., Buján, S., Couillin, I., Brough, D., Arostegui, J. I., & Pelegrín, P.
Affiliations: Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (ES)
University of Manchester (GB)
Hospital Clínic de Barcelona (ES)
Hospital Sant Joan de Déu Barcelona (ES)
Vall d'Hebron Hospital Universitari (ES)
Université d'Orléans (FR)
ORCID: Martínez, Carlos M
Compan, Vincent
Yagüe, Jordi
Antón, Jordi
Couillin, Isabelle
Brough, David
Pelegrín, Pablo
Venue: Nature Immunology
Publisher: Springer Science and Business Media LLC
Published: 2014-06-22
Volume: 15
Issue: 8
Pages: 738-748
ISSN: 1529-2908 (ISSN-L)
1529-2916
DOI: 10.1038/ni.2919
OpenAlex: W2143119237
Cited by: 790
References: 50
Citations by year: 2026: 28 · 2025: 39 · 2024: 41 · 2023: 63 · 2022: 81 · 2021: 84 · 2020: 86 · 2019: 68 · 2018: 74 · 2017: 88 · 2016: 60 · 2015: 57 · 2014: 20
FWCI: 30.77
Type: journal article
Language: en
Open access: green
hdl.handle.net
Licence: cc-by-nc-nd
www.springer.com/tdm (tdm)
Locations: Nature Immunology (publishedVersion)
PubMed (publishedVersion)
Hispana (publishedVersion, cc-by-nc-nd)
Research Explorer (The University of Manchester) (submittedVersion)
Funders: Wellcome Trust
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Health Sciences › Medicine › Hematology › Autoimmune and Inflammatory Disorders Research
Keywords: NLRP3 inflammasome, caspase-1, IL-1β processing, cryopyrin-associated periodic syndromes, macrophages, autoinflammatory disease, phagocytosis
MeSH terms: NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Carrier Proteins, Cells, Cultured, Cytoskeletal Proteins, Humans, Inflammation, Macrophages, Mice, Inbred C57BL, Phagocytosis, Signal Transduction, Mice, Knockout, Caspases, Caspase 1, Apoptosis Regulatory Proteins, Mice, CARD Signaling Adaptor Proteins, Caspases, Initiator, Interleukin-1beta, Cryopyrin-Associated Periodic Syndromes, HEK293 Cells, Inflammasomes

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The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response

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